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Autoreactive T cells target neoself-antigens in lupus
Nature Genetics ( IF 31.7 ) Pub Date : 2024-10-10 , DOI: 10.1038/s41588-024-01955-9
Kyle Vogan

Reduced expression of the invariant chain impairs antigen presentation by the major histocompatibility complex class II (MHC-II), triggering the production of autoantibodies against aberrant self-antigens, termed neoself-antigens. To further examine the impact of these processes in vivo, Mori et al. generated mice harboring an inducible knockout allele for the invariant chain. They found that ablation of the invariant chain in adult mice resulted in a lupus-like systemic phenotype, accompanied by presentation of neoself-antigens on MHC-II, activation of autoreactive B cells and T cells, and clonal expansion of neoself-reactive T cells. Next, they analyzed T cell receptor (TCR) repertoires from human patients with systemic lupus erythematosus (SLE) compared with healthy controls, and found that TCRs recognizing neoself-antigens were specifically present in patients with SLE, comprising roughly 10% of their TCR repertoire. Notably, they also found evidence that reactivation of Epstein–Barr virus (EBV), a known risk factor for SLE, resulted in decreased invariant chain expression and a corresponding increase in the presentation of neoself-antigens on MHC-II. Collectively, these results provide a plausible model linking EBV reactivation with aberrant production of neoself-antigens as an etiological trigger underlying the autoimmune processes that drive SLE.

Original reference: Cell https://doi.org/10.1016/j.cell.2024.08.025 (2024)



中文翻译:


自身反应性 T 细胞靶向狼疮中的新自身抗原



不变链表达的减少会损害主要组织相容性复合体 II 类 (MHC-II) 的抗原呈递,从而触发针对异常自身抗原的自身抗体的产生,称为新自身抗原。为了进一步检查这些过程在体内的影响,Mori 等人生成了携带不变链的诱导敲除等位基因的小鼠。他们发现,成年小鼠不变链的消融导致狼疮样全身表型,伴有 MHC-II 上新自身抗原的出现、自身反应性 B 细胞和 T 细胞的激活以及新自身反应性 T 细胞的克隆扩增。接下来,他们分析了与健康对照相比,系统性红斑狼疮 (SLE) 人类患者的 T 细胞受体 (TCR) 库,发现识别新自身抗原的 TCR 特异性存在于 SLE 患者中,约占其 TCR 库的 10%。值得注意的是,他们还发现证据表明,SLE 的已知危险因素 Epstein-Barr 病毒 (EBV) 的再激活导致不变链表达降低,并相应地增加 MHC-II 上新自身抗原的呈递。总的来说,这些结果提供了一个合理的模型,将 EBV 再激活与新自身抗原的异常产生联系起来,作为驱动 SLE 的自身免疫过程的病因触发因素。

Original reference: Cell https://doi.org/10.1016/j.cell.2024.08.025 (2024)

更新日期:2024-10-11
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